Fatty Acid Oxidation Defect (FOAD)

I. INTRODUCTION & PATHOPHYSIOLOGY

Definition: Inborn errors of mitochondrial $β$ -oxidation, a pathway essential for energy production during fasting, illness, or increased energy expenditure.
Physiologic Role:
- Switch from carbohydrate to fat metabolism during low caloric intake.
- Fatty acids are primary fuel for skeletal muscle and heart.
- Hepatic oxidation produces ketone bodies (acetoacetate, 3-hydroxybutyrate) $\to$ fuel for brain.
Pathophysiology of Defects:
- Energy Failure: Inability to produce ketones $\to$ “Hypoketotic Hypoglycemia”.
- Toxic Accumulation: Build-up of fatty acid intermediates (acyl-CoAs, acylcarnitines) causes toxicity to liver, heart, and muscle.
- Secondary Carnitine Deficiency: Acylcarnitines compete with free carnitine for renal reabsorption.

** defects in $β$ -Oxidation Cycle**:
- Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency (Most common).
- Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency.
- Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) / Mitochondrial Trifunctional Protein (MTP) Deficiency.
- Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency.
Defects in Carnitine Cycle (Transport/Entry):
- Carnitine Transporter Deficiency (Primary Carnitine Deficiency).
- Carnitine Palmitoyltransferase I (CPT-I) Deficiency.
- Carnitine-Acylcarnitine Translocase (CACT) Deficiency.
- Carnitine Palmitoyltransferase II (CPT-II) Deficiency.
Electron Transfer Defects:
- Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) / Glutaric Acidemia Type II.

A. Acute Metabolic Decompensation (Early Onset)

Triggers: Prolonged fasting (>12-16 hrs), infection, fever, weaning.
Presentation: Reye-like syndrome.
- Vomiting, lethargy, rapid progression to coma/seizures.
- Hepatomegaly (steatosis).
- Sudden Unexpected Infant Death (SUID).
- Biochemical Triad: Hypoketotic Hypoglycemia, Hyperammonemia, Mild Metabolic Acidosis (or absent acidosis due to lack of ketones).

B. Chronic/Muscular Presentation (Late Onset)

Skeletal Myopathy: Exercise intolerance, muscle pain, weakness.
Rhabdomyolysis: Recurrent, triggered by exercise/illness; myoglobinuria.
Cardiomyopathy: Dilated or hypertrophic (common in long-chain defects: VLCAD, LCHAD, CPT-II).

C. Specific Associations

Maternal Complications: HELLP syndrome or Acute Fatty Liver of Pregnancy (AFLP) in mothers carrying a fetus with LCHAD or MTP deficiency.
Retinopathy/Neuropathy: Progressive pigmentary retinopathy seen in LCHAD deficiency.
Dysmorphism: Renal cysts/brain malformations in MADD (Glutaric Acidemia II).

1. Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency

Epidemiology: Most common FAOD; strong founder effect (Northwestern European).
Genetics: ACADM gene; c.985A>G (p.Lys329Glu) is the common mutation.
Clinical:
- Presentation: 3 months to 5 years.
- Fasting intolerance causing hypoketotic hypoglycemia and sudden death.
- Prognosis: Excellent if diagnosed (newborn screening) and fasting avoided. No cardiomyopathy.

2. Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency

Genetics: ACADVL gene.
Clinical:
- Severe early infantile form: Cardiomyopathy (hypertrophic/dilated), arrhythmias, hypotonia.
- Late onset: Rhabdomyolysis, myoglobinuria.
Biochemistry: Elevated C14:1 acylcarnitine.

3. LCHAD / Mitochondrial Trifunctional Protein (MTP) Deficiency

Enzyme: MTP has 3 activities (hydratase, dehydrogenase, thiolase).
Clinical: Severe cardiomyopathy, liver disease, neuropathy, pigmentary retinopathy (unique to LCHAD).
Pregnancy History: Maternal AFLP/HELLP syndrome is a major red flag.

4. CPT-II Deficiency

Neonatal form: Fatal cardiomyopathy/arrhythmias, dysmorphism.
Adult myopathic form: Most common lipid myopathy. Exercise-induced muscle pain, rhabdomyolysis.

Screening (Acute Crisis):
- Blood Glucose: Hypoglycemia.
- Urinary Ketones: Inappropriately negative/low (“Hypoketotic”).
- Blood Gas: Mild or no acidosis (unlike organic acidemias).
- Ammonia: Hyperammonemia (transient).
- Liver Function: Elevated transaminases, prolonged PT/PTT.
- CPK: Elevated in myopathic forms.
Confirmatory Tests:
- Plasma Acylcarnitine Profile (Tandem MS): Diagnostic gold standard.
  - MCAD: Elevated C8 (Octanoyl), C6, C10:1.
  - VLCAD: Elevated C14:1.
  - LCHAD: Elevated C16-OH, C18:1-OH.
- Urine Organic Acids:
  - Dicarboxylic aciduria (adipic, suberic, sebacic acids) - non-specific but suggestive.
  - Specific conjugates (e.g., hexanoylglycine in MCAD).
- Total & Free Carnitine: Reduced free carnitine (secondary deficiency); elevated acyl/free ratio.
- Molecular Genetics: Gene sequencing (ACADM, ACADVL, etc.).

A. Acute Management (Metabolic Decompensation)

Goal: Reverse catabolism and lipolysis immediately.
IV Dextrose: Bolus 10% Dextrose (2 mL/kg) followed by high maintenance infusion (glucose infusion rate 8–10 mg/kg/min).
Monitoring: Glucose, electrolytes, ammonia, CPK.
Carnitine: Controversial in acute phase of long-chain defects (may produce toxic long-chain acylcarnitines); generally avoided acutely in VLCAD/LCHAD.

B. Chronic Management

Avoidance of Fasting:
- Infants <6 mo: No fast >4-6 hours.
- Toddlers/Children: No fast >8-12 hours.
Dietary Modification:
- MCAD: Heart-healthy diet, avoid excessive fat.
- Long-Chain Defects (VLCAD/LCHAD):
  - Fat restriction (<30% energy).
  - Supplementation with Medium-Chain Triglycerides (MCT oil) (bypasses long-chain defects).
  - Essential fatty acid supplementation (Walnut oil/Safflower oil).
Carnitine Supplementation: Used in primary carnitine deficiency and some secondary states (low dose) when free carnitine <10 $μ$ M.
Anaplerotic Therapy: Triheptanoin (C7 fatty acid) for long-chain defects (provides propionyl-CoA/succinyl-CoA for Krebs cycle).
Emergency Protocol: “Sick day regimen” with high carbohydrate intake (e.g., glucose polymer solutions) at first sign of illness.